Abstract

BACKGROUND AND OBJECTIVES:

Dose-dependent clearing of podocyte globotriaosylceramide has previously been shown in patients with classic Fabry disease treated with enzyme replacement. Our study evaluates the dose-dependent effects of agalsidase therapy in serial kidney biopsies of patients treated for up to 14 years.

DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS:

Twenty patients with classic Fabry disease (12 men) started enzyme replacement therapy at a median age of 21 (range =7-62) years old. Agalsidase-α or -β was prescribed for a median of 9.4 (range =5-14) years. The lower fixed dose group received agalsidase 0.2 mg/kg every other week throughout the follow-up period. The higher dose group received a range of agalsidase doses (0.2-1.0 mg/kg every other week). Dose changes were made due to disease progression, suboptimal effect, or agalsidase-β shortage. Serial kidney biopsies were performed along with clinical assessment and biomarkers and scored according to recommendations from the International Study Group of Fabry Nephropathy.

RESULTS:

No statistical differences were found in baseline or final GFR or albuminuria. Kidney biopsies showed significant reduction of podocyte globotriaosylceramide in both the lower fixed dose group (-1.39 [SD=1.04]; P=0.004) and the higher dose group (-3.16 [SD=2.39]; P=0.002). Podocyte globotriaosylceramide (Gb3) reduction correlated with cumulative agalsidase dose (r=0.69; P=0.001). Arterial/arteriolar intima Gb3 cleared significantly in the higher dose group, all seven patients with baseline intimal Gb3 cleared the intima, one patient gained intimal Gb3 inclusions (P=0.03), and medial Gb3 did not change statistically in either group. Residual plasma globotriaosylsphingosine levels remained higher in the lower fixed dose group (20.1 nmol/L [SD=11.9]) compared with the higher dose group (10.4 nmol/L [SD=8.4]) and correlated with cumulative agalsidase dose in men (r=0.71; P=0.01).

The course of biochemical and clinical parameters in patients during enzyme replacement therapy. Plasma globotriaosylsphingosine (lysoGb3), albumin-to-creatinine ratio, and clinical Fabry disease severity scores for the lower fixed dose and higher dose groups during enzyme replacement therapy. True baseline plasma lysoGb3 values are only available for three men in the lower fixed dose group and two women in the higher dose group. (A, C, and E) The lower fixed dose group. (B, D, and F) The higher dose group. Albuminuria due to de novo GN. The numeration of the patients corresponds to the numeration in . The same color corresponds to the same patient throughout the panels for each treatment group (i.e., the lower fixed dose and higher dose groups). *Patient in whom the clinical Fabry disease severity scores increased on agalsidase dose <1.0 mg/kg every other week. ⋆, denotes de novo GN.

Changes in podocyte globotriaosylceramide burden related to agalsidase dose. (A and C) The lower fixed dose group. (B and D) The higher dose group. Lower fixed-dose group: Agalsidase-α 0.2 mg/kg every other week, patients 11 and 17 received agalsidase-β 0.2 mg/kg every other week. Higher fixed dose group: Agalsidase-α 0.2 or 0.4 mg/kg every other week, agalsidase-β 0.5 or 1.0 mg/kg every other week, pt 13 received agalsidase-α 0.2 mg/kg every week for 6 years. Each line represents a single patient, and the color code is explained in the right margin. The numeration of the patients corresponds to the numeration in .

Different reduction of podocyte globotriaosylceramide in two brothers after 13 years of enzyme replacement therapy, with increased clearing on higher dose. Baseline and follow-up biopsies for patients 6 and 7 (sections stained with toluidine blue). Column 1 shows 2 years of agalsidase. Podocyte globotriaosylceramide (Gb3) scores are 6.9 and 7.0 for patients 6 and 7, respectively. Column 2 shows 3 years of agalsidase. Podocyte Gb3 scores are 3.6 and 7.0 for patients 6 and 7, respectively. Column 3 shows 7 years of agalsidase. Podocyte Gb3 scores are 1.8 and 7.0 for patients 6 and 7, respectively. Column 4 shows 13 years of agalsidase. Podocyte Gb3 scores are 0.15 and 7.0 for patients 6 and 7, respectively. The images show inclusions of Gb3 in podocytes (red arrows). All images in the upper panel are from patient 6. All images in the lower panel are from patient 7.